Glucosidelike compounds of the steroid series and a process of obtaining the same



Patented Aug. 10, 1943 GLUCOSIDELI'KE COMPOUNDS OF THE STEROID SERIES AND A PROCESS OF OBTAINING THE SAME Hans Herioff Inhoffen, Berlin-Wilmersdorf, Max Gehrke, Birkenwerdennear Berlin, and Walter Schoeller, Berlin-Charlottenburg, Germany, assignors to Schering Corporation, Bloomfield, N. J., a corporation of New Jersey No Drawing. Application May 3, 1939, Serial No. 271,500. In Germany May 16, 1938 '14 Claims.

This invention relates to glucoside-like derivatives of compounds of the steroid series having at least one glucosidable hydroxy. group and preferably at last one keto group in their molecule, and to a method of making the same.

It is already known to produce the glucosides of steroid compounds, in particular of sexual hormones. Thus oestradiol glucoside has already been obtained from oestrone glucoside acetate by reduction and subsequent saponification of the oestradiol glucoside acetate, or from oestradiol by way of the oestradiol glucoside acetate, although in very poor yield. Compare, for instance, Brit. Pat. 487,229, U. S. Pat. 2,088,792, German Pats. 650,089 and 654,652.

Compared with this already known process the present invention yields the reduced glucosidelike derivatives of compounds of the steroid series having at least one hydroxy group capable of being transformed into a glucoside group and at least one keto group in their molecule, in a simpler and more advantageous manner and in one working phase from the acylated glucosidelike keto-compounds of this series, by carrying out the reduction of the keto group under such conditions that hydrogenation of any double bonds that may be present in the ring system does not take place, but on the other hand a simultaneous saponification of the acyl groups attached to the sugar residue or residues is effected.

There is suitable for this purpose the process of exchange of oxidation stages between alcohols oxidizable to the corresponding oxo compounds, and particularly secondary alcohols, for example isopropyl alcohol, and oxo compounds in the presence of metal alcoholates, for example of aluminum and magnesium alcoholates, and particularly of secondary alcohols, which process has become known in priniciple from the work of Meerwein and Schmidt (Annalen der Chemie,

vol. 444, page 221) and also of Ponndorf (Zeitschriit fiir angewandte Chemie, vol. 39, page 138), (compare further also the process of Liittringhaus described in German Patent No. 384,351). By the application of this process to glucoside esters of the steroid series in a su'rprising manner a simultaneous reduction of the keto groups present and Saponification are ef- Iected.

As suitable steroids may be mentioned'for example:

Oestrone Dehydro-androsterone A -2l-hydroxy-pregnendione-3.20

A -3,21-dihydroxy-pregnenone-20 Pregnanolone, polyhydroxydione compounds of the pregnane series, such as A -11,2l-dihydroxypregnendione-3,20, the term pregnane being used in its generic sense covering saturated and unsaturated compounds and others.

This invention is illustrated by the following examples, without, however being limited to them.

Example 1 A solution of l g. of oestrone glucoside acetate and 1 gram of aluminium isopropylate in 50 ccs. of dry isopropyl alcohol is boiled under reflux for 15 hours at 110 C. bath temperature. The solution is evaporated in vacuum to dryness and the residue shaken with dilute sulphuric acid.

The precipitate is filtered with suction, washed with Water and, for the purpose of purification, dissolved in boiling Water. On cooling the filtered solution the oestradiol glucoside separates in fine needles. M. P. 225-227 C. The glucoside is soluble in alcohol, but only very little soluble in ether. Yield 0.4 gram.

Example 2 A solution of 1 gram of tetra-acetyl-glucoside of A -21-hydroxy-pregnendione-3.20, which is obtainable according to customary methods, for example according to the text book of Richter- Anschutz, Chemie der Kohlenstofiverbindungen, vol. 2, 1st half, page 359 (1935) and 2 grams of aluminium isopropylate are heated in cos. of dry isopropyl alcohol for 15 hours under a reflux condenser at bath temperature to boiling. During the last 5 hours the acetone formed is distilled oiT. The reaction mixture is brought to dryness in vacuum and the residue extracted with dilute sulphuric acid. The insoluble material is filtered with suction, washed with water and recrystallised from dilute alcohol.

There is thus obtained the A -21-glucosidopregnen-diol-3.20 as an amorphous product.

By starting from acetyl-lactosido-pregnendione there is obtained in the described manner the A -21-lactosido-pregnen-dio1-3.20.

Example 3 mannosides or rhamnosides or the like may be employed as starting materials, the corresponding glucoside-like glucosidic compounds of the steroids being produced. Of course, other equivalent starting compounds may be employed and variations from the specific conditions and proportions may be resorted to without departing from the principles of the invention.

What we claim is:

1. Process as claimed in claim 14, in which as starting material an oestrone-acylglucoside is employed.

2. Process as claimed in claim 14, 'in which as starting material oestrone-glucoside-acetate is employed.

3. Process as claimed in claim 14, in which as starting material an acyl-glucoside of dehydroandrosterone is employed.

4. Process as claimed in claim 14, in which as starting material dehydro-androsterone-glucoside-acetate is employed.

5. Process as claimed in claim 14, in which as starting material acyl glucosides of the hydroxypregnendione-series are employed.

6. Process as claimed in claim 14, in which as starting material an acyl-glucoside of a hydroxyketone compound of the pregnane series is employed.

7. Process as claimed in claim 14, in which as starting material an acyl-glucoside oi the polyhydron-pregnenon-series is employed.

8. Process as claimed in claim 14, in which as starting material an acyl-glucoside or the polyhydroxy-pregnendion-series is employed.

9. Process as claimed in claim 14, in which as starting material an acyl-glucoside of a polyhydroxy-ketone of the pregnane series is employed.

10. Process as claimed in claim 14, in which as starting material an acyl-glucoside of a polyhydroxy-dione compound of the pregnane-series is employed.

11. Process according to claim 14, wherein the acyl-steroid-glucoside contains more than one acylated mono-saccharide residue bound in the form oi. glucoside.

12. Process as claimed in claim 14, in which the metal alcoholate is aluminium isopropylate.

13. Process for the manufacture of an oestradiol-glucoside, comprising heating oestrone glucoside acetate with aluminium isopropylate in isopropyl alcohol, and separating and purifying the oestradiol glucoside formed.

14. Process for the manufacture of glucosidelike derivatives of diol compounds of the steroid series comprising heating an acyl derivative of a glusosidic compound of the steroid series containing at least one carbonyl group in the molecule with a saturated monohydric alcohol capable of oxidation to the corresponding oxo compound, and with a member of the group consisting of aluminium and magnesium alcoholates, until reduction of the carbonyl group and saponification have taken place, the acyl group being that of a carboxylic acid.

HANS HERLOFF INHOFFEN. MAX GEHRKE. WALTER SCHOELLER. 

